(3aR,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate | 301187-46-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3aR,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate
• 英文别名: [(3aR,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-3a,4,7,7a-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yl] 2,2,2-trichloroethanimidate
• CAS: 301187-46-2
• 化学式: C₁₁H₁₄Cl₃NO₆
• 分子量: 362.594
• InChiKey: FWPYNYDRGPZEKJ-CUWOBHIPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  87.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3aR,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate 在 三氟化硼乙醚 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 N-(2-(3-bromopropoxy)-7-(((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-8-methylquinolin-3-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide
  参考文献：
  名称：

  Synthesis and biological evaluation of coumarin replacements of novobiocin as Hsp90 inhibitors

  摘要：

  Since Hsp90 modulates all six hallmarks of cancer simultaneously, it has become an attractive target for the development of cancer chemotherapeutics. In an effort to develop more efficacious compounds for Hsp90 inhibition, novobiocin analogues were prepared by replacing the central coumarin core with naphthalene, quinolinone, and quinoline surrogates. These modifications allowed for modification of the 2-position, which was previously unexplored. Biological evaluation of these compounds suggests a hydrophobic pocket about the 2-position of novobiocin. Anti-proliferative activities of these analogues against multiple cancer cell lines identified 2-alkoxyquinoline derivatives to exhibit improved activity. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.12.056
• 作为产物：
  描述：

  (+)-6-deoxy-5-C,4-O-dimethyl-L-xylo-hexopyranose 在 caesium carbonate 作用下， 以 二氯甲烷 为溶剂， 生成 (3aR,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate
  参考文献：
  名称：

  异硫氰酸盐2,2-二氧化物和1,2-苯并恶臭素2,2-二氧化物回旋酶B抑制剂的合成

  摘要：

  描述了陀螺酶B香豆素抑制剂的异硫氰酸盐2,2-二氧化物和1,2-苯并恶臭素2,2-二氧化物类似物的设计，合成和体外生物学评估。与香豆素衍生物相比，1,2-苯并恶臭素2,2-二氧化物系列化合物在松弛DNA促旋酶的负超螺旋中显示出更高的抑制能力。

  DOI：

  10.1016/s0040-4039(00)00044-7

文献信息

• NOVOBIOCIN ANALOGUES AND TREATMENT OF POLYCYSTIC KIDNEY DISEASE
  申请人：Calvet James P.

  公开号：US20110082098A1

  公开（公告）日：2011-04-07

  Novobiocin analogues are useful in methods of treating, inhibiting, and/or preventing cyst formation in autosomal dominant polycystic kidney disease (ADPKD) in a subject. The disclosure provides methods of treating ADPKD comprising administering a therapeutically effective amount of a coumarin-3-carboxamide novobiocin analogue. Accordingly, the method can include administering a novobiocin analogue in a therapeutically effective amount for reducing levels of mTOR pathway phosphoproteins P-mTOR, P-Akt and P-S6K, or combinations thereof. Further, the method can include administering a novobiocin analogue in a therapeutically effective amount for reducing levels of Hsp-90 client proteins CFTR, ErbB2, c-Raf and Cdk4, or combinations thereof.

  新比奴霉素类似物在治疗、抑制和/或预防自体显性多囊肾病（ADPKD）中的囊肿形成方法中是有用的。本公开提供了治疗ADPKD的方法，包括给予香豆素-3-羧酰胺新比奴霉素类似物的治疗有效量。因此，该方法可以包括给予新比奴霉素类似物的治疗有效量，以降低mTOR途径磷酸化蛋白P-mTOR、P-Akt和P-S6K的水平，或其组合。此外，该方法可以包括给予新比奴霉素类似物的治疗有效量，以降低Hsp-90客体蛋白CFTR、ErbB2、c-Raf和Cdk4的水平，或其组合。
• [EN] C-TERMINAL HSP90 INHIBITORS<br/>[FR] INHIBITEURS DE HSP90 C-TERMINAUX
  申请人：UNIV KANSAS

  公开号：WO2013119985A1

  公开（公告）日：2013-08-15

  Hsp90 C-terminal inhibitors and pharmaceutical compositions containing such compounds are provided. The compounds of the disclosure are useful for the treatment and/or prevention of neurodegenerative disorders such as diabetic peripheral neuropathy.

  Hsp90 C端抑制剂及含有此类化合物的药物组合物。本发明公开的化合物可用于治疗和/或预防神经退行性疾病，如糖尿病周围神经病变。
• Synthesis and Evaluation of Coumermycin A1 Analogues that Inhibit the Hsp90 Protein Folding Machinery
  作者：Joseph A. Burlison、Brian S. J. Blagg

  DOI：10.1021/ol061918j

  日期：2006.10.1

  antibiotics are not only potent inhibitors of DNA gyrase but also represent the most effective C-terminal inhibitors of 90 kDa heat shock proteins (Hsp90) reported thus far. In contrast to the N-terminal ATP-binding site, little is known about the Hsp90 C-terminus. In addition, very limited structure-activity relationships exist between this class of natural products and Hsp90. In this letter, the syntheses

  香豆素抗生素不仅是DNA促旋酶的有效抑制剂，而且是迄今为止报道的最有效的90 kDa热休克蛋白（Hsp90）C端抑制剂。与N端ATP结合位点相反，对Hsp90 C端的了解很少。此外，这类天然产物与Hsp90之间存在非常有限的构效关系。在这封信中，介绍了二聚香豆素类似物的合成及其在乳腺癌细胞系中的抑制作用。
• A Library of Noviosylated Coumarin Analogues
  作者：Yung-Tzung Huang、Brian S. J. Blagg

  DOI：10.1021/jo062083t

  日期：2007.5.1

  The DNA gyrase inhibitor, novobiocin, was recently shown to inhibit Hsp90 via a previously unrecognized C-terminal ATP-binding site. Previous structure−activity relationship studies identified key moieties that appear important for Hsp90 inhibitory activity. In an effort to provide a more efficacious lead compound, a parallel library of noviosylated coumarin analogues was prepared.

  最近发现，DNA促旋酶抑制剂novobiocin可通过以前无法识别的C端ATP结合位点抑制Hsp90。以前的结构活性关系研究确定了对Hsp90抑制活性似乎很重要的关键部分。为了提供更有效的先导化合物，制备了诺维磺化香豆素类似物的平行文库。
• Development of noviomimetics that modulate molecular chaperones and manifest neuroprotective effects
  作者：Leah K. Forsberg、Mercy Anyika、Zhenyuan You、Sean Emery、Mason McMullen、Rick T. Dobrowsky、Brian S.J. Blagg

  DOI：10.1016/j.ejmech.2017.10.038

  日期：2018.1

  further explore the development of noviomimetics and evaluate their efficacy using a luciferase refolding assay, immunoblot analysis, a c-jun assay, and an assay measuring mitochondrial bioenergetics. These new noviomimetics were designed and synthesized and found to induce Hsp70 and improve biological activity. Noviomimetics 39e and 40a were found to induce Hsp70 and exhibit promising effects in cellular

  热休克蛋白90（Hsp90）是一种正在研究中的用于治疗癌症和神经退行性疾病的伴侣蛋白。衍生自新霉素（novologues）的神经保护性Hsp90 C-末端抑制剂包括KU-32和KU-596。这些创新分子调节分子伴侣，并导致热休克蛋白70（Hsp70）的诱导。与酚醛清毒剂KU-596和KU-32相比，“拟诺维制剂”用一个简单的环己基部分取代了合成复杂的酚醛新糖，以保持生物学功效。在这项研究中，我们进一步探索仿拟药物的开发，并使用荧光素酶复性测定，免疫印迹分析，c-jun测定和测量线粒体生物能的测定来评估其功效。这些新的仿拟药物是经过设计和合成的，可诱导Hsp70并改善其生物学活性。仿拟药物发现39e和40a在细胞测定中诱导Hsp70并显示出有希望的作用。